Abstract The NIAID has named the development of a universal influenza vaccine as one if its key research goals, and this need will not be met with traditional vaccine design. The design of a globally protective vaccine against influenza has been hampered by the lack of a clear and definable correlate of immunity against influenza. The current correlate of protection from influenza infection, used to evaluate seasonal influenza vaccines, is the hemagglutination inhibition (HAI) titer, an indirect measure of virus neutralization by antibodies. However, HAI incompletely explains protection from seasonal influenza infection in humans. Conversely, extra-neutralizing antibody-dependent innate immune effector functions, including antibody dependent cellular cytotoxicity (ADCC), antibody dependent phagocytosis (ADCP), and antibody dependent complement activation (ADC), have all been implicated in protection in mice. However, it is uncertain whether non-neutralizing functions contribute to protection in humans. Thus, here we aim to exploit a comprehensive, agnostic, sample-sparing humoral profiling tool - that broadly captures Fc-profile diversity at unprecedented depths - to define the extra-neutralizing profiles of antibodies that track with protection against influenza in humans. Two unique cohorts of well characterized vaccinees will be profiled to define correlates of protection and correlates of the evolution of neutralizing antibody breadth. Linked to mechanistic dissection in mice, correlates will be dissected to define mechanistic links to guide the development of next generation vaccine strategies aimed at inducing functional-broadly neutralizing antibodies against influenza.